Project Summary/Abstract: The widely accepted model proposes that the infralimbic cortex (IL) is a key structure for fear extinction that plays no role in fear conditioning. Surprisingly, we found that selectively decreasing expression of FK506 binding protein 5 (FKBP5) in IL reduced acquisition and recall of conditioned fear. Although clinical data suggest that FKBP5 plays a role in PTSD, it is unclear whether differences in FKBP5 expression alone could predispose or protect individuals from the development of PTSD. Our data suggests that higher expression of FKBP5 in the ventral medial prefrontal cortex (equivalent of IL in humans) could predispose people to the development of PTSD following trauma. Since direct stimulation of IL inputs in the amygdala do not reduce fear acquisition, the reduced fear acquisition after knocking down IL FKBP5 is likely to be mediated by IL projections to other subcortical structures. The acquisition of conditioned fear requires glucocorticoid and beta adrenergic receptor stimulation in the basolateral amygdala. Therefore, IL could modulate fear learning by modulating glucocorticoid or catecholamine release via inputs to the lateral hypothalamus (LHA), bed nucleus of the stria terminalis (BNST), or nucleus tractus solitarius (NTS). In this project, we will test the novel hypothesis that signaling via Fkpb5 modulates fear learning and memory by modulating the excitability of IL projections to the BNST, LHA, or NTS. To test this hypothesis, we will first evaluate whether reducing or overexpressing FKBP5 selectively in IL projection neurons modulates acquisition or recall of conditioned fear. Next, we will evaluate whether FKBP5 modulates the intrinsic or synaptic excitability of IL neurons projecting to the BNST, LHA, or NTS using patch-clamp recordings of retrogradely labeled IL projections in brain slices. Finally we will use optogenetics to evaluate whether IL inputs to the BNST, LHA, or NTS modulate fear learning and memory.